Mice with dysfunctional TGF-β signaling develop altered intestinal microbiome and colorectal cancer resistant to 5FU

BIOCHIMICA ET BIOPHYSICA ACTA-MOLECULAR BASIS OF DISEASE

卷:1867

Article

Wang, Zhanhuai^1,2  Hopson, Lindsay M.³  Singleton, Stephanie S.³  Yang, Xiaochun^1,4,5  Jogunoori, Wilma⁶  Mazumder, Raja³  Obias, Vincent⁷  Lin, Paul¹  Nguyen, Bao-Ngoc⁸  Yao, Michael⁹  Miller, Larry⁹  White, Jon⁷  Rao, Shuyun^1,4,5  Mishra, Lopa^1,4,5 

[1] George Washington Univ, Ctr Translat Med, Dept Surg, Washington, DC USA

[2] Zhejiang Univ, Affiliated Hosp 2, Minist Educ,Sch Med, Dept Colorectal Surg & Oncol,Key Lab Canc Prevent, Hangzhou, Zhejiang, Peoples R China

[3] George Washington Univ, Dept Biochem & Mol Med, Washington, DC USA

[4] Northwell Hlth, Inst Bioelect Med, Feinstein Inst Med Res, 350 Community Dr, Manhasset, NY 11030 USA

[5] Northwell Hlth, Cold Spring Harbor Lab, Dept Med, Div Gastroenterol & Hepatol, Manhasset, NY 11030 USA

[6] Vet Affairs Med Ctr, Res & Dev, Washington, DC USA

[7] George Washington Univ, Dept Surg, Washington, DC USA

[8] Vet Affairs Med Ctr, Dept Gastroenterol, Washington, DC USA

[9] Zucker Sch Med Hofstra Northwell Hlth Syst, Dept Med, Div Gastroenterol, New Hyde Pk, NY USA

关键词: Chemoresistance;    Microbiome;    Colorectal cancer;    TGF-beta signaling;    Bacteroides;    5FU;   

DOI  :  10.1016/j.bbadis.2021.166179

来源: Elsevier

【 摘 要 】

Emerging data show a rise in colorectal cancer (CRC) incidence in young men and women that is often chemoresistant. One potential risk factor is an alteration in the microbiome. Here, we investigated the role of TGF-beta signaling on the intestinal microbiome and the efficacy of chemotherapy for CRC induced by azoxymethane and dextran sodium sulfate in mice. We used two genotypes of TGF-beta-signaling-deficient mice (Smad4(+/-) and Smad4(+/-) Sptbn1(+/-)), which developed CRC with similar phenotypes and had similar alterations in the intestinal microbiome. Using these mice, we evaluated the intestinal microbiome and determined the effect of dysfunctional TGF-beta signaling on the response to the chemotherapeutic agent 5-Fluoro-uracil (5FU) after induction of CRC. Using shotgun metagenomic sequencing, we determined gut microbiota composition in mice with CRC and found reduced amounts of beneficial species of Bacteroides and Parabacteroides in the mutants compared to the wild-type (WT) mice. Furthermore, the mutant mice with CRC were resistant to 5FU. Whereas the abundances of E. boltae, B.dorei, Lachnoclostridium sp., and Mordavella sp. were significantly reduced in mice with CRC, these species only recovered to basal amounts after 5FU treatment in WT mice, suggesting that the alterations in the intestinal microbiome resulting from compromised TGF-beta signaling impaired the response to 5FU. These findings could have implications for inhibiting the TGF-beta pathway in the treatment of CRC or other cancers.

【 授权许可】

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